Derivatives of 5-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, their preparation and their therapeutic application

ABSTRACT

Compounds complying with the general formula 
                         
in which R either represents a halogen atom or a phenyl group substituted by one or more groups chosen from halogen atoms and (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, amino, trifluoromethyl, cyano, hydroxy, acetyl or methylenedioxy groups, or represents a pyridinyl group, a thienyl group, an indolyl group, or a pyrimidinyl group optionally substituted by one or more (C 1 -C 6 )alkoxy groups, where, of the two carbon-carbon bonds represented by  , one is single and the other may be single or double. The compounds of this invention are useful as therapeutic agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/500,015, filed Jun. 23, 2004, now allowed, which was the NationalStage of International application No. PCT/FR03/00,004, filed Jan. 3,2003, both of which are incorporated herein by reference in theirentirety; which claims the benefit of priority of French PatentApplication No. 02/00,109, filed Jan. 7, 2002.

The present invention relates to compounds which are ligands fornicotinic receptors and which are useful in the treatment or theprevention of disorders linked to a dysfunction of nicotinic receptors,in particular at the central nervous system level.

The compounds of the present invention comply with the general formula(I)

in which R represents a halogen atom or a (C₃-C₆)cycloalkyl group or aphenyl group substituted by one or more groups chosen from a halogenatom, or a (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, amino, (C₁-C₃)dialkylamino, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, acetylor methylenedioxy group, or a piperidinyl, or morpholin-4-yl, orpyrrolidin-1-yl, or azetidin-1-yl, or azepin-1-yl, or pyridinyl, orquinolinyl, or thienyl, or pyrazinyl, or furyl, or benzofuryl, orbenzothienyl, or indolyl, or pyrimidinyl, or isoxazolyl, orphenoxazinyl, or phenoxathiinyl, or dibenzothienyl, or dibenzofuryl, orpyrrolyl, or naphthyl group, where each of these groups may optionallybe substituted by one or more groups chosen from halogen atoms,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethoxy, trifluoromethyl, nitro,cyano, hydroxy, amino, (C₁-C₃)dialkylamino or (C₃-C₈) cycloalkylaminogroups.

Of the two carbon-carbon bonds represented by

,

one is single and the other may be single or double. Furthermore, thecarbon atom in position 5 is asymmetric, and therefore the compounds mayexist in the form of two enantiomers or of mixtures of these latter.

The compounds of the invention may exist in the form of bases or ofsalts derived from addition to acids.

A subset of preferred compounds is that of the compounds of generalformula (I) in which R either represents a halogen atom or a phenylgroup substituted by one or more groups chosen from halogen atoms and(C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, amino, trifluoromethyl, cyano,hydroxy, acetyl or methylenedioxy groups, or represents a pyridinylgroup, or a thienyl group, or an indolyl group, or a pyrimidinyl groupoptionally substituted by one or more (C₁-C₆) alkoxy groups.

The compounds of the general formula (I) may be prepared by a processillustrated by the following scheme. 3-Oxo-1,4-azabicyclo[2.2.2]octane,of formula (II), is reacted with a pyridine derivative of generalformula (III), in which R is as defined above and W represents a halogenatom.

It is also possible to carry out a condensation reaction between3-oxo-1-azabicyclo[2.2.2]octane and the lithiated derivative of thecompounds of general formula (III) obtained by halogen-metal exchangewith an alkyl lithium derivative.

This gives compounds of general formula (IV) which, when treated withheat in an acid medium lead to compounds of the general formula (I) inwhich one of the two carbon-carbon bonds represented by

, is double. Catalytic hydrogenation of the double bond leads tocompounds of general formula (I) in which all the bonds of theazabicyclooctane ring are saturated.

3-Oxo-1-azabicyclo[2.2.2]octane is commercially available.

The compounds of general formula (III) are commercially available or areaccessible by methods described in the literature.

For certain compounds, the substituents R are not present in thestarting compound of general formula (III); depending on their nature,these substituents may be introduced on the final compound of generalformula (I). Thus, for example, compounds of general formula (I) inwhich R represents an aryl group may be prepared starting fromcorresponding compounds in whose formula R represents a halogen atom,using any of the known methods, such as Suzuki coupling in the presenceof a boronic acid and of a palladium catalyst, e.g.tetrakis(triphenylphosphine)palladium, or Stille coupling with theappropriate reactants.

The following examples illustrate the preparation of some compounds ofthe invention.

Elemental microanalyses and IR and NMR spectra confirm the structures ofthe compounds obtained.

The numbers indicated in brackets in the titles of the examplescorrespond to those in the first column of the table below.

In the names of the compounds, the hyphen “-” is part of the word,whereas the underscore “_” serves merely as the break at the end of aline, and is to be deleted in the absence of a break, and must not bereplaced by a standard hyphen or by a space.

EXAMPLE 1 Compound No. 1 Hydrobromide of5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (2:1) 1.1.5-Bromo-2-phenylpyridine

30 g (0.127 mol) of 2,5-dibromopyridine in suspension in 100 ml oftoluene, 15.4 g (0.127 mol) of phenylboronic acid, 4.4 g (0.0038 mol) oftetrakis(triphenylphosphine)palladium, 90 ml of a 2M aqueous solution ofsodium carbonate and 4 ml of ethanol are introduced in succession into a500 ml three-necked flask, and the mixture is heated at 90° C. for 22 h.

The mixture is decanted, the organic phase is washed with 100 ml ofwater and dried and concentrated under reduced pressure, and the residueis purified by chromatography on a silica gel column, eluting with a30/70 mixture of cyclohexane and dichloromethane.This gives 22.4 g of crystals.Melting point: 69-72° C.

1.2. 3-Hydroxy-3-(2-phenylpyridin-5-yl)-1-azabicyclo[2.2.2]octane

2.5 g (0.0107 mol) of 5-bromo-2-phenylpyridine in solution in 40 ml ofethyl ether are introduced into a 100 ml three-necked flask, and thereaction mixture is cooled to −60° C. before dropwise addition during 10minutes of 5.6 ml (0.0139 mol) of a 2.5 M solution of n-butyllithium inhexane, and the temperature is held at −70° C. for 1 h.

1.34 g (0.0107 mol) of 1-azabicyclo[2.2.2]octan-3-one in solution in 20ml of tetrahydrofuran is added during 10 min, and the mixture is stirredfor 30 min at −70° C. then at ambient temperature for 4 h.

The reaction mixture is hydrolyzed by adding 100 ml of methanol and isconcentrated under reduced pressure.

The residue is taken up in 100 ml of a saturated aqueous solution ofammonium chloride and the aqueous phase is extracted with chloroform.The organic phases are dried and concentrated under reduced pressure andthe residue is purified by chromatography on a silica gel column,eluting with a 90/10/1 mixture of chloroform, methanol and ammonia. Thisgives 0.8 g of crystals.Melting point: 214° C.

1.3. Hydrobromide of5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (2:1)

0.8 g (2.85 mmol) of3-hydroxy-3-(2-phenylpyridin-5-yl)-1-azabicyclo[2.2.2]octane and then 10ml of methanesulfonic acid are introduced into a 25 ml three-neckedflask and the mixture is heated to 180° C. for 24 h.

The mixture is poured onto ice and rendered alkaline by adding aconcentrated aqueous solution of sodium hydroxide, the aqueous phase isextracted with chloroform, and the organic phase is dried andconcentrated under reduced pressure. The residue is purified bychromatography on a silica gel column, eluting with a 98/2/0.2 mixtureof chloroform, methanol and ammonia.This gives 0.25 g of product, the dihydrobromide of which is made byadding a 5.7 M solution of hydrobromic acid in acetic acid.This gives 0.22 g of dihydrobromide.Melting point: 273-274° C.

EXAMPLE 2 Compound No. 2 Hydrobromide of5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]octane (2:1)

0.14 g (0.33 mmol) of dihydrobromide of5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene in solution in 20ml of methanol are introduced into a 250 ml Parr bottle, and 0.14 g ofpalladium, 10% adsorbed on carbon, is added. The reaction mixture isthen submitted to a pressure of 0.35 MPa of hydrogen, with stirring, for5 h.

The catalyst is recovered via filtration through diatomaceous earth andthe solvent is concentrated under reduced pressure.

This gives 0.058 g of product.

Melting point: 272-277° C.

EXAMPLE 3 Compound No. 8 Ethanedioate of5-[2-(3-methylphenyl)pyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (1:1)3.1. 3-Hydroxy-3-(2-bromopyridin-5-yl)-1-azabicyclo[2.2.2]octane

27.6 g (0.116 mol) of 2,5-dibromopyridine in 1 000 ml of ethyl ether areintroduced into a 2 000 ml three-necked flask, the reaction mixture iscooled to −67° C. and 56 ml (0.140 mol) of a 2.5 M solution ofbutyllithium in hexane are added dropwise in 10 min.

The mixture is stirred at −67° C. for 45 min before adding 14.5 g (0.116mol) of 1-azabicyclo[2.2.2]octan-3-one in solution in 150 ml of ethylether in 45 min, and the mixture is stirred at −67° C. for 3 h.

300 ml of a saturated aqueous solution of ammonium chloride are addedfollowed by 200 ml of a concentrated aqueous solution of sodiumhydroxide, the aqueous phase is extracted with chloroform, and theorganic phases are dried and concentrated under reduced pressure. Theresidue is purified by chromatography on a silica gel column, elutingwith a 95/5/0.5, then 80/15/1.5, mixture of chloroform, methanol andammonia.This gives 19.7 g of product in the form of amorphous solid.

3.2. 5-(2-bromopyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene

9.4 g (0.033 mol) of3-hydroxy-3-(2-bromopyridin-5-yl)-1-azabicyclo[2.2.2]octane and 35 ml ofconcentrated sulfuric acid are introduced into a 100 ml three-neckedflask and the mixture is heated at 190° C. for 1 h 45.

The mixture is cooled and poured onto 400 ml of an ice-cold aqueoussodium hydroxide solution, the aqueous phase is extracted withchloroform, and the organic phases are dried and evaporated underreduced pressure.

The residue is purified by chromatography on a silica gel column,eluting with a 90/10/1 mixture of chloroform, methanol and ammonia.

This gives 3.9 g of product in the form of a pale yellow solid.

Melting point: 73-75° C.

3.3. Ethanedioate of5-[2-(3-methylphenyl)pyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (1:1)

0.2 g (0.75 mmol) of5-(2-bromopyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene, 3 ml of toluene,0.7 ml of a 2 M aqueous solution of sodium carbonate, 0.147 g (1.05mmol) of 3-methylbenzeneboronic acid, 0.042 g (0.04 mmol) oftetrakis(triphenylphosphino)palladium and 0.7 ml of ethanol areintroduced in succession into a 10 ml tube and the mixture is heated at100° C. for 15 h.

The aqueous phase is removed by decanting and the crude product isextracted on a DOWEX® (ion exchange resin) resin column by washing insuccession with methanol and then chloroform before eluting with asolution of ammonia. The residue is purified by chromatography on asilica gel column, eluting with a 90/10/1 mixture of chloroform,methanol and ammonia. This gives 0.167 g of product in the form of oil,which is dissolved in 2 ml of isopropyl alcohol to form an ethanedioateby adding 0.051 g (0.057 mmol) of ethanedioic acid in solution inisopropyl alcohol. This gives 0.188 g of crystallized product.Mp: 173-174° C.

EXAMPLE 4 Compound No. 26 Hydrobromide of5-[2-(3-fluorophenyl)pyridin-5-yl)-1-azabicyclo[3.2.1]octane 2:1

0.18 g (0.51 mmol) of the ethanedioate of5-[2-(3-fluorophenyl)pyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene insolution in 20 ml of methanol are introduced into a 250 ml Parr bottle,and 0.36 g of palladium, 10% adsorbed on carbon, is added, and thereaction mixture is submitted to a pressure of 0.42 MPa of hydrogen,with stirring, at 45° C. for 6 h.

The catalyst is recovered by filtration on diatomaceous earth, thefiltrate is concentrated under reduced pressure, the residue is taken upin 10 ml of an N aqueous solution of sodium hydroxide, and the aqueousphase is extracted with chloroform, and the crude product is purified bychromatography on a silica gel column, eluting with a 80/20/2 mixture ofchloroform, methanol and ammonia. This gives 0.085 g of product, thedihydrobromide of which is made by adding 0.107 ml of a 33% solution ofhydrobromic acid in acetic acid. This gives 0.097 g of crystals.Melting point: 98-100° C.

The table which follows illustrates the chemical structures and thephysical properties of some compounds of the invention. In the column“R”, “(+)” indicates the dextrorotatory enantiomer and “(−)” thelaevorotatory enantiomer; the compounds not annotated in that column areracemates. In the “=” column, the number indicated corresponds to theposition of the double bond in the case of a 1-azabicyclooctene, and “−”indicates a saturated heterocycle. In the “salt” column, “−” indicates acompound in the form of a base, “HBr” indicates a hydrobromide and “ox.”indicates an oxalate. The corresponding molar acid:base ratios areindicated. In the column “M(° C.)”, “(d)” indicates a melting point withdecomposition.

TABLE (I)

No. R = Salt M(° C.)  1 C₆H₅ 3 HBr 2:1 273-274  2 C₆H₅ — HBr 2:1 272-277 3 C₆H₅ 2 HBr 2:1 297-305  4 2,4-(OCH₃)₂-5-pyrimidinyl 2 HBr 2:1 340 (d) 5 3,4-(OCH₃)₂-C₆H₃ 3 HBr 2:1 261-262  6 3,4-(OCH₃)₂-C₆H₃ — HBr 2:1234-236  7 2-F—C₆H₄ 3 ox. 1:1 157-158  8 3-CH₃—C₆H₄ 3 ox. 1:1 173-174  93-F—C₆H₄ 3 ox. 1:1 163-164 10 3-NO₂—C₆H₄ 3 ox. 1:1 183-184 11 3-CF₃—C₆H₄3 ox. 1:1 156-157 12 4-CH₃—C₆H₄ 3 ox. 1:1 213-215 13 3-Thienyl 3 ox. 1:1189-190 14 3,4-OCH₂O—C₆H₃ 3 ox. 1:1 201-202 15 4-Cl—C₆H₄ 3 ox. 1:1201-203 16 3-CH₃CO—C₆H₄ 3 ox. 1:1 155-156 17 3-Pyridinyl 3 ox. 1:1183-184 18 5-Indolyl 3 ox. 1:1 253-254 19 4-CH₃O—C₆H₄ 3 ox. 1:1 205-20720 3,5-(CH₃)₂—C₆H₃ 3 ox. 1:1 192-193 21 4-Pyridinyl 3 ox. 1:1 172-174 224-CH₃O—C₆H₄ — HBr 2:1 246-247 23 4-CH₃—C₆H₄ — HBr 2:1 295-297 243-CH₃—C₆H₄ — HBr 2:1 284-287 25 3,5-(CH₃)₂—C₆H₃ — HBr 2:1 250-254 263-F—C₆H₄ — HBr 2:1  98-100 27 3-Thienyl — HBr 2:1 193-196 283,4-OCH₂O—C₆H₃ — HBr 2:1 260-263 29 2-F—C₆H₄ — HBr 2:1 266-269 303-Pyridinyl — HBr 3:1 256-260 31 4-Pyridinyl — HBr 2:1 249-253 323-NO₂—C₆H₄ — HBr 3:1 264-267 33 3-CF₃—C₆H₄ — HBr 2:1 218-221 34 Br 3 HBr2:1 234-236 35 Br 2 HBr 2:1 >350 36 4-Piperidinyl — HBr 3:1 289-292 373-Piperidinyl — HBr 3:1 261-265 38 4-CH₃O—C₆H₄ (+) — — 125-129 394-CH₃O—C₆H₄ (−) — — 125-129 40 3-F—C₆H₄ (+) — — 68-70 41 3-F—C₆H₄ (_) —— 68-70 42 2-Thienyl — HBr 2:1 251 (d) 43 2-Thienyl 3 HBr 2:1 246-247 445-CH₃-2-thienyl 3 HBr 2:1 237-238 45 5-CH₃-2-thienyl — HBr 2:1 210-21146 5-Cl-2-thienyl — HBr 2:1 248-250 47 5-Cl-2-thienyl 3 HBr 2:1 258-25948 2-Furyl 3 HBr 2:1 262-264 49 2-Furyl — HBr 2:1 182 (d) 50 5-Indolyl —ox. 1:1 268-269 51 2-Benzofuryl 3 — 145-146 52 2-Benzofuryl — HBr 2:1303-305 53 2-Pyrrolyl 3 HBr 2:1 265-266 54 2-Pyrrolyl — ox. 1:1 95-97 552-Benzothienyl 3 — 165-166 56 2-Benzothienyl — HBr 2:1 311-313 573-Furyl 3 HBr 2:1 291-294 58 3-Furyl — HBr 2:1 313-315 594-OH-3-pyridinyl — HBr 2:1 268-270 60 3,5-(CH₃)₂-1,2-oxazol-4-yl — —116-117 61 3,5-(CH₃)₂-1,2-oxazol-4-yl 3 HBr 2:1 250-252 622,4-(CH₃O)₂-pyrimidin-5-yl — ox. 1:1 70-72 63 4-CH₃-2-thienyl — HBr 2:1336-338 64 4-CH₃-2-thienyl 3 HBr 2:1 284-285 65 1-Dibenzofuryl — HBr 2:1188-189 66 1-Dibenzofuryl 3 HBr 2:1 302-304 67 1-Phenoxathiinyl 3 HBr2:1 292-293 68 1-Phenoxathiinyl — HBr 1:1 200-203 69 8-Quinoleinyl — HBr2:1 206-208 70 8-Quinoleinyl 3 HBr 2:1 309-310 71 3-Benzothienyl 3 HBr2:1 222-223 72 3-Benzothienyl — ox. 1:1 80-82

The compounds of the present invention have been studied for theiraffinity in relation to nicotinic receptors containing the α₄β₂ subunit,using the methods described by Anderson and Arneric in Eur. J.Pharmacol. (1994), 253, 261 and by Hall et al. in Brain Res. (1993),600, 127. Male Sprague Dawley rats weighing from 150 to 200 g aredecapitated and the entire brain is rapidly removed, homogenized in 15volumes of a 0.32 M sucrose solution at 4° C. and then centrifuged at 1000 g for 10 min. The pellet is removed and the supernatant iscentrifuged at 20 000 g for 20 min at 4° C. The pellet is recovered andhomogenized with the aid of a Polytron™ mill in 15 volumes ofdoubly-distilled water at 4° C., then centrifuged at 8 000 g for 20 min.The pellet is removed and the supernatant and the skin layer (buffycoat) are centrifuged at 40 000 g for 20 min, and the pellet isrecovered and suspended in 15 ml of doubly-distilled water andcentrifuged again at 40 000 g prior to storage at −80° C. On the day ofthe experiment, the tissue is slowly defrosted and is suspended in 3volumes of buffer. 150 μl of this membrane suspension are incubated at4° C. for 120 min in the presence of 100 μl of 1 nM [³H]-cytisine in afinal volume of 500 μl of buffer, in the presence or absence of testcompound.

The reaction is halted by filtration through Whatman GF/B™ filterspretreated with polyethyleneimine, the filters are rinsed twice, eachtime with 5 ml of buffer at 4° C., and the radioactivity retained on thefilter is measured by liquid scintigraphy. The nonspecific binding inthe presence of 10 μM (−)-nicotine is determined; the nonspecificbinding represents from 75 to 85% of the total binding recovered on thefilter.For each concentration of compound studied, the percentage of inhibitionof the specific binding of [³H]-cytisine is determined, and then theIC₅₀ value, the concentration of compound which inhibits 50% of thespecific binding, is calculated.The IC₅₀ values for the highest-affinity compounds of the invention arefrom 0.01 to 10 μM.

The compounds of the invention were also studied for their affinity inrelation to nicotinic receptors containing the α₇ subunit, using themethods described by Mark and Collins in J. Pharmacol. Exp. Ther.(1982), 22, 564 and by Marks et al. in Mol. Pharmacol. (1986), 30, 427.

Male OFA rats weighing from 150 to 200 g are decapitated and the entirebrain is rapidly removed, homogenized in 15 volumes of a 0.32 M sucrosesolution at 4° C. and then centrifuged at 1 000 g for 10 min. The pelletis removed and the supernatant is centrifuged at 8 000 g for 20 min at4° C. The pellet is recovered and homogenized with the aid of aPolytron™ mill in 15 volumes of doubly-distilled water at 4° C., thencentrifuged at 8 000 g for 20 min. The pellet is removed and thesupernatant and the skin layer (buffy coat) are centrifuged at 40 000 gfor 20 min, and the pellet is recovered and suspended in 15 ml ofdoubly-distilled water and centrifuged again at 40 000 g prior tostorage at −80° C. On the day of the experiment, the tissue is slowlydefrosted and is suspended in 5 volumes of buffer. 150 μl of thismembrane suspension are preincubated at 37° C. for 30 min in darkness inthe presence or absence of the test compound. The membranes are thenincubated for 60 min at 37° C. in darkness in the presence of 50 μl of 1nM [³H]α-bungarotoxin in a final volume of 250 μl of 20 mM HEPES buffer,0.05% polyethyleneimine. The reaction is halted by filtration throughWhatman GF/C™ filters pretreated for 3 h with 0.05% polyethyleneimine.The filters are rinsed twice, each time with 5 ml of buffer at 4° C.,and the radioactivity retained on each filter is measured by liquidscintigraphy. The nonspecific binding in the presence of 1 μMα-bungarotoxin is determined; the nonspecific binding representsapproximately 60% of the total binding recovered on the filter. Thepercentage of inhibition of the specific binding of [³H]α-bungarotoxinis determined for each concentration of studied compound and then theIC₅₀ value, the concentration of compound which inhibits 50% of thespecific binding, is calculated.The IC₅₀ values of the highest-affinity compounds of the invention arefrom 0.005 to 20 μM.

The above results show that the compounds of the invention are ligandsfor nicotinic receptors. Certain of them are selective for receptorscontaining α₇ subunits and others are of mixed nature for receptors ofα₄β₂ and α₇ type.

The results of the tests suggest the use of the compounds in thetreatment or the prevention of disorders linked to dysfunction of thenicotinic receptors, in particular at the central nervous system level.

These disorders comprise detrimental cognitive changes, morespecifically detrimental memory changes, and also detrimentalattentional changes, linked to Alzheimer's disease, to pathologicalageing (age-associated memory impairment, AAMI), to Parkinsoniansyndrome, to trisomy 21 (Down's syndrome), to Korsakoff's alcoholicsyndrome or to vascular dementias (multi-infarct dementia, MDI).

The compounds of the invention could also be useful in the treatment ofmotor disorders observed in Parkinson's disease or of other neurologicaldiseases, such as Huntington's chorea, Tourette's syndrome, tardivedyskinesia and hyperkinesia.

The compounds of the invention may also constitute a curative orsymptomatic treatment for acute neurodegenerative pathologies, such asstrokes and cerebral hypoxic episodes, and chronic neurodegenerativepathologies, such as Alzheimer's disease and Parkinson's disease. Theymay be used in cases of psychiatric pathology: schizophrenia,depression, anxiety, panic attacks, or compulsive or obsessionalbehavior.

They can prevent symptoms due to withdrawal from tobacco or alcohol, orvarious addictive substances, such as cocaine, LSD, cannabis,benzodiazepines.

The present invention therefore also provides pharmaceuticalcompositions comprising an effective dose of at least one compound ofthe invention, in the form of base or of salt or of pharmaceuticallyacceptable solvate, or in a mixture, where appropriate with suitableexcipients.

The choice of the said excipients depends on the desired mode ofadministration and the pharmaceutical format.

The pharmaceutical compositions of the invention may therefore beintended for oral, sublingual, subcutaneous, intramuscular, intravenous,topical, intratracheal, intranasal, transdermic, rectal, or intraocularadministration.

Examples of possible unitary administration forms are tablets, gelatincapsules, granules, powders, solutions or suspensions to be taken orallyor to be injected, transdermal patches or suppositories. Ointments,lotions and collyria can be envisaged for topical administration.

The said unitary forms are dosed to permit daily administration of from0.01 to 20 mg of active principle per kg of body weight, depending onthe pharmaceutical dosage form.

To prepare tablets, the following materials are added to the activeprinciple, micronized or non-micronized: a pharmaceutical vehicle, whichcan be composed of diluents, such as lactose, starch, ormicrocrystalline cellulose, or formulation adjuvants, such as binders(polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like), flowagents, such as silica, lubricants, such as magnesium stearate, stearicacid, glycerol tribehenate, sodium stearylfumarate. Wetting orsurface-active agents, such as sodium lauryl sulfate, can also be added.

Possible preparation techniques are direct tableting, dry granulation,wet granulation or hot melt.

The tablets can be uncoated, sugar-coated, for example with sucrose, orcoated with various polymers or other appropriate materials. They can bedesigned to permit rapid, delayed or sustained release of the activeprinciple by virtue of polymer matrices or of specific polymers used inthe coating.

To prepare gelatin capsules, the active principle is mixed with drypharmaceutical vehicles (simple mixing, dry or wet granulation, or hotmelt), or liquid or semisolid pharmaceutical vehicles.

The gelatin capsules can be hard or soft and may have a thin filmcoating, so as to have rapid, sustained or delayed activity (forexample, for an enteric form).

A composition in the form of a syrup or an elixir or for administrationin the form of drops can comprise the active principle in conjunctionwith a sweetener, preferably a calorie-free sweetener, methylparaben orpropylparaben, as antiseptic, a flavor enhancer and a colorant.

The water-dispersible granules and powders may comprise the activeprinciple in a mixture with the dispersing or wetting agents, ordispersing agents such as polyvinylpyrrolidone, and also with sweetenersand flavor-improvers.

For rectal administration, use is made of suppositories prepared withbinders which melt at rectal temperature, for example cocoa butter orpolyethylene glycols.

For parenteral administration, use is made of aqueous suspensions,isotonic saline solutions or injectable sterile solutions comprisingpharmacologically compatible dispersing agents and/or wetting agents,for example propylene glycol or butylene glycol.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives or elsewith a polymer matrix or with a cyclodextrin (transdermal patches orsustained release forms).

The topical compositions of the invention comprise a medium compatiblewith the skin. They can be provided in particular in the form ofaqueous, alcoholic or aqueous/alcoholic solutions, of gels, ofwater-in-oil or oil-in-water emulsions having the appearance of a creamor of a gel, of microemulsions or of aerosols, or in the form ofvesicular dispersions comprising ionic and/or nonionic lipids. Thesepharmaceutical dosage forms are prepared by methods conventional in therelevant fields.

Finally, the pharmaceutical compositions of the invention may comprise,in addition to a compound of general formula (I), other activeprinciples which can be of use in the treatment of the disorders anddiseases indicated above.

1. A compound selected from the group consisting of:5-[2-(2,4-dimethoxy-5-pyrimidinyl)-pyridin-5-yl]-1-azabicyclo[3.2.1]oct-2-enehydrobromide (2:1);5-[2-(3,4-dimethoxyphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(3,4-dimethoxyphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(2-fluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(3-methylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(3-fluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(3-nitrophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(3-trifluoromethylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(4-methylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(3-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-ene ethanedioate(1:1);5-[2-(1,3-benzodioxol-5-yl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(4-chlorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);1-{3-[5-(1-azabicyclo[3.2.1]oct-3-en-5-yl)pyridin-2-yl]phenyl}ethanoneethanedioate (1:1);5-[2-(3-pyridinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(5-indolyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-ene ethanedioate(1:1); 5-[2-(4-methoxyphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(3,5-dimethylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(4-pyridinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-eneethanedioate (1:1);5-[2-(4-methoxyphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(4-methylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3-methylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3,5-dimethylphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3-fluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1);5-[2-(1,3-benzodioxol-5-yl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(2-fluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3-pyridinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-[2-(4-pyridinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3-nitrophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-[2-(3-trifluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1); 5-[2-bromopyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1); 5-[2-bromopyridin-5-yl]-1-azabicyclo[3.2.1]oct-2-enehydrobromide (2:1);5-[2-(4-piperidinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-[2-(3-piperidinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);(+)-5-[2-(4-methoxyphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane;(−)-5-[2-(4-methoxyphenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane;(+)-5-[2-(3-fluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane;(−)-5-[2-(3-fluorophenyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane;5-[2-(2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-[2-(2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(5-methyl-2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(5-methyl-2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(5-chloro-2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(5-chloro-2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(2-furyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-ene hydrobromide(2:1); 5-[2-(2-furyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(5-indolyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane ethanedioate(1:1); 5-[2-(2-benzofuryl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;5-[2-(2-benzofuryl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-[2-(2-pyrrolyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(2-pyrrolyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane ethanedioate(1:1); 5-[2-(2-benzothienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;5-[2-(2-benzothienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3-furyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-ene hydrobromide(2:1); 5-[2-(3-furyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(4-hydroxy-3-pyridinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(3,5-dimethyl-1,2-oxazol-4-yl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane;5-[2-(3,5-dimethyl-1,2-oxazol-4-yl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(2,4-dimethoxypyrimidin-5-yl)pyridin-5-yl]-1-azabicyclo[3.2.1]octaneethanedioate (1:1);5-[2-(4-methyl-2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(4-methyl-2-thienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(1-dibenzofuryl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(1-dibenzofuryl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(1-phenoxatiinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(1-phenoxatiinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octanehydrobromide (2:1);5-[2-(8-quinoleinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-[2-(8-quinoleinyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(3-benzothienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]oct-3-enehydrobromide (2:1);5-[2-(3-benzothienyl)pyridin-5-yl]-1-azabicyclo[3.2.1]octaneethanedioate (1:1).
 2. A compound selected from the group consisting of:5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]oct-3-ene hydrobromide(2:1); 5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]octane hydrobromide(2:1); 5-(2-phenylpyridin-5-yl)-1-azabicyclo[3.2.1]oct-2-enehydrobromide (2:1).